Abstract P5-03-09: LINC00624 binding with SFPQ/MATR3/ NONO protein complexes enhances resistance to neoadjuvant therapy in HER-2 positive breast cancer by inhibiting tumor immune response

Abstract

Abstract Background Neoadjuvant chemotherapy(NAC) has been widely used for its ability to downstage breast cancer. With anti-HER2 therapy, around half of the HER2 positive patients achieve pCR after NAC. However, treatment failure is still a concern and leads to a worse prognosis. New biomarkers and biological mechanisms are waiting to be discovered to tackle this problem. Methods RNA-Seq was performed to identify differently expressed RNAs between pCR and non-pCR group. The IC50 value was measured by CCK-8 assay in HER-2 positive cells (SK-BR-3 and JIMT-1). Quantitative RT-PCR (qRT-PCR) was used to detect the expression levels of LINC00624 and its potential target genes. RNA-seq and GSEA analysis was carried out to determine the target pathways regulated by LINC00624. Results Core needle biopsy tissue from HER-2 positive patients was collected before NAC. LINC00624 was found to be down regulated in pCR group compared with non-pCR group by RNA-seq. High expression of LINC00624 was associated with poor overall survival in TCGA database and our own patients cohort. Overexpression of LINC00624 promoted cell proliferation and colony-forming ability. Meanwhile, the IC50 values of Paclitaxel and Trastuzumab in HER-2 positive breast cells were decreased by LINC00624. Via RNA pull-down assay and mass spectrometry, the SFPQ/MATR3/NONO protein complex, which was reported to be associated with the innate immune system, was found to interact with LINC00624. RNA-seq further revealed that several immunological and inflammatory factors, including 'IFN-α response', 'IFN-γ response' and 'TNF-α via NF-κB' were suppressed by LINC00624. IFN downstream molecules were inactivated in LINC00624 overexpressing cells following TNF-α, IFN-α, IFN-β and poly (I:C) treatment, which implies the immune inhibition ability of LINC00624 . Conclusion LINC00624 is associated with resistance to NAC in HER-2 positive breast cancer. It binds with the SFPQ/MATR3/NONO complex and desensitizes cell response to chemotherapy and anti-HER2 agents via suppressing immunological and inflammatory effect. This study suggests that LINC00624 could serve as a biomarker to predict therapy response to NAC in HER-2 positive breast cancer. Citation Format: Zhang Q, Xiu B, Chi Y, Chi W-R, Wu J. LINC00624 binding with SFPQ/MATR3/ NONO protein complexes enhances resistance to neoadjuvant therapy in HER-2 positive breast cancer by inhibiting tumor immune response [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-09.